This project's objective is to identify the role of enteroglucagon as a humoral mediator of intestinal adaptation. The intestine has long been known to exhibit two distinct types of adaptation. First, intestinal mucosal mass increases, and hence absorption of all nutrients increases, under many conditions associated with increased energy needs leading to hyperphagia. Second, specific intestinal transporters are up- or down-regulated by changes in dietary levels or body stores of their substrates. Strongly suggestive but not conclusive evidence makes it likely that enteroglucagon is a (the?) humoral mediator of the former response, and may also contribute to the latter response in the case of dietary carbohydrate effects on intestinal glucose transporters. Hence this project will test enteroglucagon's role in adaptation by means of in vivo studies in rats, employing critical tests that could not be carried out until recently because of lack of knowledge of endogenous enteroglucagon forms, their limited availability for in-vivo testing, and inadequate assays. One approach will be to test the effects of chronic infusions of two enteroglucagon peptides, oxyntomodulin and GLP-1 7-36 amide, on mucosal growth and on intestinal nutrient uptake. The other approach will be to test the effect of immunoneutralizing enteroglucagon on both types of adaptation in two rat models that this laboratory developed. One of the models produces a several-fold increase in mucosal mass, the other a two-fold increase in glucose transporter activity. The health relatedness of this project derives from the role of intestinal adaptation in important clinical conditions, such as diabetes, short bowel syndrome, pregnancy, lactation, and exercise.